3/25/2009 @ 6:00AM

Dendreon Disclosure May Endanger Provenge Study

Has
Dendreon
, a money-losing drug developer, imperiled the main study of its experimental prostate cancer treatment Provenge?

On Oct. 6, Dendreon
put out a press release that sent its shares up 33% in a day. Provenge appeared to cut patients’ death rates by 20% compared with a placebo treatment, the company said. The release also contained statistical details that made good results seem likely when final results are released in April.

But four top statisticians now say Dendreon may have compromised the integrity of the trial by putting out the release. They say it was unorthodox for Dendreon to even know such a detailed result, much less to publicize it. The danger: The company, patients or doctors might have changed what they were doing once they knew how the study was going. If the final outcome is only marginally statistically significant, it might be tossed, putting Dendreon and its drug back at square one.

Janet Wittes of the Statistics Collaborative, a company that works with drug makers, also says she was also “shocked” by Dendreon’s actions. “When we as a company are serving as the reporting statisticians for a trial and a company asks for this sort of information, we refuse to release it.”

Normally, only a secretive committee of hand-selected scientists would be privy to the analysis unless it showed Provenge was either so effective or so dangerous that the study needed to be stopped immediately. For Dendreon to get and publicize the results appears to violate section 6.3 of Food and Drug Administration guidance issued in March 2006.

Dendreon says its actions were cleared by the FDA but declined to make researchers or executives available to provide further explanation. The FDA says it is legally forbidden from commenting on experimental drugs. Meanwhile, Chief Executive Mitch Gold has been using the data to talk up Provenge. “We’re clearly within shooting range,” Gold told analysts at a JP Morgan investor conference in January. “Sometimes I use a football analogy where we are on the 10-yard line and we are in the red zone, and we need to punch it in the end zone right now.”

Dendreon’s future is riding on Provenge. The company has only one other drug in clinical trials and, as of its last quarterly report, it had just $102 million in cash; the company posted a $70 million annual loss for the year. If the main study of Provenge does not succeed, it may be difficult for Dendreon to mount another big clinical trial to prove the drug works.

At the January conference Gold said it was “a very exciting time for us, and a very exciting time for patients” because the results would be in very soon. In the past two years, the company has traded as high as $22 and as low as $3.

Provenge was already controversial. In March 2007, a panel of FDA-selected experts voted 13 to four that the treatment, which aims to use the immune system to fight off cancer cells, was effective. But several prominent researchers wrote letters to the FDA arguing that the data so far did not meet the minimum requirements needed for approval. The studies on Provenge so far had failed on their main goals, but seemed to show the therapy prolongs life.

In May 2007, the FDA told Dendreon it would need more data to get Provenge approved. That put the focus on a 500-person study called IMPACT, which was already underway and aimed to show that Provenge reduced the risk of death compared with a sham treatment in men whose prostate cancer had spread to their bones or lymph nodes.

Dendreon had always planned to have the independent data safety monitoring board (DSMB) for the trial take a look at the data before the study ended. In March 2008, Dendreon announced that it was reducing the statistical power of that analysis in order to shorten the IMPACT trial by one year. At the time, the company said it had OK’d its strategy with regulators via a Special Protocol Assessment (SPA), in which the FDA agrees the study will answer its outstanding questions.

If the interim analysis for IMPACT had shown an unambiguous result, that would have been enough to get Provenge approved, but it didn’t meet that high hurdle.

What was unexpected was that the DSMB gave the full data to Dendreon and released it to the world. When asked if this could potentially compromise the trial, Thomas Fleming, a statistician at the University of Washington, said that it could.

Dendreon says that the decision to get the data from the DSMB and share it with the public was approved by the FDA as part of its SPA. It also says it showed its Oct. 6 press release to the agency.

But the actual text of SPA agreements is not disclosed to the public, and in the past companies have lost out because of technicalities. In 2007,
GPC Biotech
repeatedly insisted that its experimental drug was covered by an SPA, only to have it revealed that one key measure of the drug’s success was not included in the agreement. The medicine was never approved.

Fleming says that the existence of the SPA does not change his opinion. The statisticians are left scratching their heads at the data release.

“I have no idea what their rationale would have been,” says Susan Ellenberg, a statistician at the University of Pennsylvania. “I can’t rule out the possibility that they did have a reason I’d be comfortable with, but I can’t think what it might be.”